The chemical modification of a biologically active drug to give a new chemical from which the active drug can be generated by enzymatic action is an important strategy to target drug action to specific cells and tissues and thereby decrease toxicity or side effects on non-target cells. N. Bodor et al., 22 Ann. Rep. Med. Chem. 303-313 (1987); T. Krenitsky et al., 81 P.N.A.S. USA 3209-3213 (1984); J. Hjelle et al., 229 J. Pharmacol. Exp. Ther. 372-380 (1984); S. Magnan et al., 25 J. Med. Chem. 1018-1021 (1982); M. Orlowski et al., 212 J. Pharmacol. Exp. Ther. 167-172 (1980). The disclosure of these articles and of all other articles listed herein are incorporated by reference as if fully set forth herein. Such compounds are known as "prodrugs".
In A. Elfarra et al. FASEB Journal, Abstract 4922 (Mar. 20, 1988) our laboratory reported that S-(6-purinyl)-L-cysteine, the cysteine derivative of the anti-tumor and immunosuppressant drug 6-mercaptopurine, could be a potential prodrug. In this regard, 6-mercaptopurine is known to be effective in the treatment of various types of tumors. However, it is not actively transported from the G.I. tract, and is readily metabolized by xanthine oxidase to generate biologically inactive metabolites. Thus, it must be given in large doses for a long time to be effective. The concept is that the .beta.-lyase needed to release the 6-mercaptopurine is predominantly found in the kidney. Further, the kidney transport system tends to concentrate amino acid derivatives. This development is of great importance since currently there is no satisfactory chemotherapy technique for treating kidney tumors. While this S-(6-purinyl)-L-cysteine approach had some success, even greater specificity is desired. Further, 6-mercaptopurine may have certain disadvantages for some patients which renders use of 6-thioguanine alternatives desirable.
In separate work, our laboratory has reported that gamma-glutamyl transpeptidase, cysteinyl glycine dipeptidase, and cysteine conjugate .beta.-lyase are all present in the kidney and may cooperatively act to release an S-(1,2-dichlorovinyl) thio moiety from S-(1,2-dichlorovinyl glutathione). A. Elfarra et al., 35 Biochem. Pharm. 283-288 (1986). Also, it has been reported that the renal acylase and the renal esterase are prevalent in the kidney.
It has also been reported in A. Elfarra et al., 83 P.N.A.S. U.S.A. 2667, 2670 (1986) that a homocysteine S-conjugate of dichlorovinyl could undergo transamination in the kidney to yield the corresponding 2-keto acid, and that non-enzymatic elimination under the conditions present in the kidney would then release the dichlorovinyl group. The S-conjugate of the hydroxy analogue is also toxic as it is metabolized to the keto-acid in the kidney by amino acid oxidases. See L. Lash et al. 276 Arch. Biochem. Biophys. 322 (1990).
Thus, it can be seen that a need exists for the development of more specific kidney prodrugs.